Clinical Pharmacokinetics Lecture 3

A state where the rate of drug administration equals the rate of drug elimination, resulting in a constant drug concentration in the body.

The relationship between drug dose and plasma concentration is directly proportional. Doubling the dose doubles the concentration.

When the dose-concentration relationship is not directly proportional. Changes in dose may lead to disproportionate changes in plasma concentration.

A method to detect non-linear pharmacokinetics. If the plot of steady-state concentration (Css) versus dose is NOT a straight line, the drug follows non-linear kinetics.

The maximum rate at which an enzyme can catalyze a reaction. Represents the point where the enzyme is fully saturated with substrate.

The concentration of substrate at which the reaction rate is half of Vmax. It indicates the affinity of the enzyme for its substrate.

A mathematical model that describes enzyme kinetics. It helps predict how a drug's concentration changes over time when it is metabolized by a saturable enzyme.

A type of non-linear pharmacokinetics where the enzyme responsible for drug elimination becomes saturated with the drug. This can lead to unexpected and potentially harmful concentration increases.

A type of pharmacokinetics where the rate of elimination doesn't increase proportionally with increasing drug concentration. This happens when the enzyme responsible for metabolizing the drug is saturated, leading to a plateau in elimination.

The maximum rate at which an enzyme can metabolize a drug. This represents the upper limit of drug elimination.

When a drug induces its own metabolism, leading to a faster rate of elimination and lower steady-state serum concentrations.

When drug binding to plasma proteins reaches its limit, leading to a higher free drug concentration and potentially increased drug effects.

The process of drug elimination from the body, typically through metabolism and excretion.

The study of how the body affects a drug, including absorption, distribution, metabolism, and elimination.

A measure of the concentration of a drug required to achieve half the maximum effect (Vmax).

Represents the maximum rate at which an enzyme can catalyze a reaction. It's the highest rate of metabolism possible.

The rate of drug elimination changes depending on the drug concentration. When concentrations are low, the enzyme works linearly, but as concentrations increase, the enzyme becomes saturated and the rate slows down.

Clearance is not constant but dependent on the concentration of the drug. As the concentration increases, clearance decreases. This happens because the enzyme is getting saturated.

It implies that a drug's elimination rate is not constant but depends on the drug concentration.

With a higher concentration, a higher dosage is needed to achieve the same effect because the enzyme system is nearing saturation.

Dosing drugs with saturable metabolism is complex because of the variability between individuals.

It is a model that describes how the rate of an enzymatic reaction changes with different substrate concentrations.

The rate of drug elimination is directly proportional to the plasma drug concentration. This means that the higher the drug concentration, the faster the drug is eliminated from the body.

When the drug concentration is much higher than the Km value, the enzyme system becomes saturated and can't metabolize the drug any faster. The rate of metabolism becomes constant.

The Michaelis-Menten constant (Km) represents the drug concentration at which the rate of metabolism is half of the maximum rate.

Some drugs can switch from first-order to zero-order kinetics when their concentration becomes very high, exceeding the enzyme's capacity.

Phenytoin is an example of a drug that exhibits mixed-order kinetics, switching from first-order to zero-order at therapeutic concentrations.

Theophylline is an example of a drug that switches from first-order to zero-order kinetics at high, toxic concentrations.

The volume of distribution (V) is unaffected by saturable metabolism and is still determined by the physiological volume of blood (VB) and tissues (VT) as well as the unbound (free) concentration of drug in the blood (fB) and tissues (fT): V = VB + (fB/fT)VT.

The half-life (t1/2) is still related to clearance and volume of distribution using the same equation as for linear pharmacokinetics: t1/2 = 0.693/K t1/2 = (0.693 ⋅ V)/Cl. Since clearance is dose- or concentration-dependent, half-life also changes with dosage or concentration changes.

As doses or concentrations increase, clearance decreases and half-life becomes longer for the drug. ↑t1/2 = (0.693 ⋅ V)/↓Cl.

Phenytoin is an example of a drug which commonly has a Km value within or below the therapeutic range, the average Km value is about 4 mg/L.

The normally effective plasma concentrations for phenytoin are between 10 and 20 mg/L. Therefore it is quite possible for patients to be overdosed due to drug accumulation.

At low concentration the apparent half-life is about 12 hours, whereas at higher concentration it may well be much greater than 24 hours. Dosing every 12 hours, the normal half-life, can rapidly lead to dangerous accumulation.

At concentrations above 20 mg/L elimination maybe very slow in some patients. Dropping for example from 25 to 23 mg/L in 24 hours, whereas normally you would expect it to drop from 25 to 12.5 to 6 mg/L in 24 hours.

For a drug that is only removed by metabolism via one enzyme system, The Michaelis-Menten equation can be used to compute the maintenance dose (MD) required to achieve a target steady- state serum concentration (Css), at steady sate, the rate of elimination is equal to the drug dosing rate (R) : MD (R) = Vmax.Css/ Km+ Css